The overall objective of this proposal is to elucidate mechanisms by which vitamin D influences prostate cancer risk. Strong evidence from experimental studies indicates that vitamin D is involved in key carcinogenesis- related processes including gene transcription, cellular differentiation, T-cell mediated immunity, cell cycle control, proliferation and apoptosis. Results from previous studies of serum [25(OH)D] and prostate cancer risk have been inconsistent. Limitations from these studies include small sample sizes, potential contamination of the comparison (control) group with preclinical cancers and the inability to investigate the extent to which circulating concentrations of [25(OH)] with vitamin D-related processes at the level of prostate tissue. With regard to genetic evidence, few polymorphisms in vitamin D related genes have been investigated. Previous studies mainly focused on a few polymorphisms in the vitamin D receptor (VDR), a critical mediator of vitamin D effects; however, recent resequencing data showed that 25 tagging polymorphisms are needed to capture the genetic variation in this large gene. Other relevant candidate genes, including those important for vitamin D activation [27-hydroxylase (CYP27A1), 1-1-hydroxylase (CYP27B1)], co-activation (NCOA1-3, SMAD3), deactivation [24-hydroxylase (CYP24A1)], transport [vitamin D binding protein encoded by group- specific component (GC)], and vitamin D signaling [retinoid X receptors (RXRA, RXRB, RXRG)] have not been sufficiently studied in relation to prostate cancer risk. We propose a nested case-control study (1800 cases and 1800 controls) to be conducted in the Prostate Cancer Prevention Trial (PCPT). As primary aims, we will investigate both circulating [25(OH)D] and genetic variability in the vitamin D pathway, including their interaction, in relation to prostate cancer risk. Importantly, we will also examine expression of VDR and RXR in prostate tissue from cases and controls and whether circulating [25(OH)D] predicts vitamin D expression in the prostate. We will also investigate whether the intervention-effect of finasteride (the active drug used in PCPT) on prostate cancer risk differs in men with low vs. high serum vitamin D or in men with or without polymorphisms in vitamin D pathway genes. Secondary aims will explore interactions of the vitamin D and androgen pathways in relation to prostate cancer and whether vitamin D biomarkers or genes influence measures of proliferation or apoptosis in prostate biopsy specimens from both cases and controls. All PCPT participants underwent a prostate biopsy with central pathology review to determine case or control status. We will investigate serum concentrations of [25(OH)D] with total and high-grade (Gleason > 7) prostate cancer. We will use tagSNPs to examine the variability in the following vitamin D pathway genes in relation to total and high-grade prostate cancer: VDR, CYP27A1, CYP27B1, CYP24A1, GC, RXRA, RXRB, RXRG, NCOA1-3, SMAD3. This project will provide important data on prostate cancer etiology with relevant translational potential, particularly regarding who might benefit most from use of finasteride for prostate cancer prevention. PUBLIC HEALTH RELEVANCE: Prostate cancer is the most commonly diagnosed cancer among men and the second leading cause of male cancer deaths in the United States. Due to the high degree of stress and anxiety men face when making treatment decisions and the exorbitant health care expenditures for treatment, prevention of prostate cancer is an important objective. This study will investigate the role of vitamin D (both biomarkers of status and genetic variation) in relation to prostate cancer risk. Our ultimate goal is to gain information for use in translational programs of prostate cancer prevention and treatment.